Plumbagin Triggers Cuproptosis in Hepatocellular Carcinoma (HCC) via the DNA‐Methyltransferase 1 (DNMT1)/microRNA‐302a‐3p (miR‐302a‐3p)/ATPase Copper Transporting Beta (ATP7B) Axis
ABSTRACT Induction of cuproptosis in tumor cells is an emerging direction for cancer drug development. Plumbagin (PLB), a natural biological molecule, has anticancer activities, partially via copper‐dependent mechanisms. But it remains unclear if PLB can induce cuproptosis in hepatocellular carcinom...
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2025-08-01
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| Online Access: | https://doi.org/10.1002/mco2.70312 |
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| author | Chuyu Wang Hao Wang Chong Wang Tongtong Tian Anli Jin Yu Liu Ran Huo Te Liu Baishen Pan Wei Guo Wenjing Yang Beili Wang |
| author_facet | Chuyu Wang Hao Wang Chong Wang Tongtong Tian Anli Jin Yu Liu Ran Huo Te Liu Baishen Pan Wei Guo Wenjing Yang Beili Wang |
| author_sort | Chuyu Wang |
| collection | DOAJ |
| description | ABSTRACT Induction of cuproptosis in tumor cells is an emerging direction for cancer drug development. Plumbagin (PLB), a natural biological molecule, has anticancer activities, partially via copper‐dependent mechanisms. But it remains unclear if PLB can induce cuproptosis in hepatocellular carcinoma (HCC). In this study, PLB showed HCC‐suppressive activities and caused representative molecular phenotypes of cuproptosis, whereas tetrathiomolybdate, an inhibitor of cuproptosis, could alleviate these effects the most. The mRNA and protein expression levels of the primary hepatic copper exporter, ATPase copper transporting beta (ATP7B), decreased in PLB‐treated HCC cells, which might cause the accumulation of intracellular copper and trigger cuproptosis. An upstream ATP7B‐regulatory microRNA, microRNA‐302a‐3p (miR‐302a‐3p), was identified by quantification and validated by the overexpression/inhibition experiment and luciferase reporter assay. Moreover, PLB was found to reduce the protein level of DNA‐methyltransferase 1 (DNMT1), thereby enhancing the promoter hypomethylation and the expression of miR‐302a‐3p. Gene manipulation experiments further demonstrated that ATP7B, miR‐302a‐3p, and DNMT1 mediated PLB‐induced cuproptosis. Preliminary clinical analyses showed that low ATP7B expression levels were associated with better prognosis, supporting the importance of ATP7B‐lowering therapeutic strategies in HCC. Together, our results indicate that PLB triggers HCC cuproptosis via the DNMT1/miR‐302a‐3p/ATP7B axis, providing a potential therapeutic strategy for HCC. |
| format | Article |
| id | doaj-art-283368a37aca42ab938588b65a22194c |
| institution | Kabale University |
| issn | 2688-2663 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
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| series | MedComm |
| spelling | doaj-art-283368a37aca42ab938588b65a22194c2025-08-20T03:43:34ZengWileyMedComm2688-26632025-08-0168n/an/a10.1002/mco2.70312Plumbagin Triggers Cuproptosis in Hepatocellular Carcinoma (HCC) via the DNA‐Methyltransferase 1 (DNMT1)/microRNA‐302a‐3p (miR‐302a‐3p)/ATPase Copper Transporting Beta (ATP7B) AxisChuyu Wang0Hao Wang1Chong Wang2Tongtong Tian3Anli Jin4Yu Liu5Ran Huo6Te Liu7Baishen Pan8Wei Guo9Wenjing Yang10Beili Wang11Department of Laboratory Medicine Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Laboratory Medicine Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Laboratory Medicine Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Laboratory Medicine Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Laboratory Medicine Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Laboratory Medicine Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Laboratory Medicine Zhongshan Hospital Fudan University Shanghai ChinaShanghai Geriatric Institute of Chinese Medicine Shanghai University of Traditional Chinese Medicine Shanghai ChinaDepartment of Laboratory Medicine Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Laboratory Medicine Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Laboratory Medicine Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Laboratory Medicine Zhongshan Hospital Fudan University Shanghai ChinaABSTRACT Induction of cuproptosis in tumor cells is an emerging direction for cancer drug development. Plumbagin (PLB), a natural biological molecule, has anticancer activities, partially via copper‐dependent mechanisms. But it remains unclear if PLB can induce cuproptosis in hepatocellular carcinoma (HCC). In this study, PLB showed HCC‐suppressive activities and caused representative molecular phenotypes of cuproptosis, whereas tetrathiomolybdate, an inhibitor of cuproptosis, could alleviate these effects the most. The mRNA and protein expression levels of the primary hepatic copper exporter, ATPase copper transporting beta (ATP7B), decreased in PLB‐treated HCC cells, which might cause the accumulation of intracellular copper and trigger cuproptosis. An upstream ATP7B‐regulatory microRNA, microRNA‐302a‐3p (miR‐302a‐3p), was identified by quantification and validated by the overexpression/inhibition experiment and luciferase reporter assay. Moreover, PLB was found to reduce the protein level of DNA‐methyltransferase 1 (DNMT1), thereby enhancing the promoter hypomethylation and the expression of miR‐302a‐3p. Gene manipulation experiments further demonstrated that ATP7B, miR‐302a‐3p, and DNMT1 mediated PLB‐induced cuproptosis. Preliminary clinical analyses showed that low ATP7B expression levels were associated with better prognosis, supporting the importance of ATP7B‐lowering therapeutic strategies in HCC. Together, our results indicate that PLB triggers HCC cuproptosis via the DNMT1/miR‐302a‐3p/ATP7B axis, providing a potential therapeutic strategy for HCC.https://doi.org/10.1002/mco2.70312ATPase copper transporting beta (ATP7B)cuproptosisDNA‐methyltransferase 1 (DNMT1)hepatocellular carcinoma (HCC)plumbagin (PLB) |
| spellingShingle | Chuyu Wang Hao Wang Chong Wang Tongtong Tian Anli Jin Yu Liu Ran Huo Te Liu Baishen Pan Wei Guo Wenjing Yang Beili Wang Plumbagin Triggers Cuproptosis in Hepatocellular Carcinoma (HCC) via the DNA‐Methyltransferase 1 (DNMT1)/microRNA‐302a‐3p (miR‐302a‐3p)/ATPase Copper Transporting Beta (ATP7B) Axis MedComm ATPase copper transporting beta (ATP7B) cuproptosis DNA‐methyltransferase 1 (DNMT1) hepatocellular carcinoma (HCC) plumbagin (PLB) |
| title | Plumbagin Triggers Cuproptosis in Hepatocellular Carcinoma (HCC) via the DNA‐Methyltransferase 1 (DNMT1)/microRNA‐302a‐3p (miR‐302a‐3p)/ATPase Copper Transporting Beta (ATP7B) Axis |
| title_full | Plumbagin Triggers Cuproptosis in Hepatocellular Carcinoma (HCC) via the DNA‐Methyltransferase 1 (DNMT1)/microRNA‐302a‐3p (miR‐302a‐3p)/ATPase Copper Transporting Beta (ATP7B) Axis |
| title_fullStr | Plumbagin Triggers Cuproptosis in Hepatocellular Carcinoma (HCC) via the DNA‐Methyltransferase 1 (DNMT1)/microRNA‐302a‐3p (miR‐302a‐3p)/ATPase Copper Transporting Beta (ATP7B) Axis |
| title_full_unstemmed | Plumbagin Triggers Cuproptosis in Hepatocellular Carcinoma (HCC) via the DNA‐Methyltransferase 1 (DNMT1)/microRNA‐302a‐3p (miR‐302a‐3p)/ATPase Copper Transporting Beta (ATP7B) Axis |
| title_short | Plumbagin Triggers Cuproptosis in Hepatocellular Carcinoma (HCC) via the DNA‐Methyltransferase 1 (DNMT1)/microRNA‐302a‐3p (miR‐302a‐3p)/ATPase Copper Transporting Beta (ATP7B) Axis |
| title_sort | plumbagin triggers cuproptosis in hepatocellular carcinoma hcc via the dna methyltransferase 1 dnmt1 microrna 302a 3p mir 302a 3p atpase copper transporting beta atp7b axis |
| topic | ATPase copper transporting beta (ATP7B) cuproptosis DNA‐methyltransferase 1 (DNMT1) hepatocellular carcinoma (HCC) plumbagin (PLB) |
| url | https://doi.org/10.1002/mco2.70312 |
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